The progressive loss of the regulation of cellular differentiation by epithelial cells can result in cancer. Retinoic acid and some of its analogues (retinoids) have been investigated as "chemopreventive" agents, that is, agents that interfere with tumor promotion in epithelial cells. Boutwell, R. K., et al, Advances in Enzyme Regulation V.17 Ed. Weber, G., Pergamon Press (1979); Verma, A. K., et al, Cancer Res (1979) 39:419-427; Dawson, M. I., et al, J Med Chem (1981) 24:583-592.
The Dawson, M. I., et al article reports the preparation of (1E,3E)- and (1Z,3E)-1-(4-carboxyphenyl)-2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3-butadiene, the methyl and ethyl esters thereof, (E)-1-(2-carboxyphenyl)4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3, 5-hexatriene and the methyl ester thereof, (E)-1-[2-(tetrahydropyranyloxy)phenyl]-4-methyl-6-(2,6,6-trimethyl-1-cyclo hexen-1-yl)-1,3,5-hexatriene and the (1E,3Z,5E) isomer thereof. Some of these aromatic retinoic acid analogues exhibited biological activity in the ornithine decarboxylase (ODC) assay, which assay is described by Verma, A. K. and Boutwell, R. K., Cancer Res (1979) 37:2196-2201.
In commonly owned copending application Ser. No. 434,622, filed Oct. 15, 1982, the syntheses of two naphthoic retinoids, methyl 6-[2-(2,6,6-trimethyl-1-cyclohexen-1-yl)ethenyl]-2-naphthoate and 6-[2-(2,6,6-trimethyl-1-cyclohexen-1-yl)ethenyl]-2-naphthoic acid, are described. The latter compound also exhibited activity in the ODC assay.
Other reported aromatic retinoic acid analogues with biological activity are 4-[(E)-2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl)-1-propen- 1-yl]benzoic acid and esters and amides thereof. These compounds exhibit a very marked therapeutic effect against carcinogen-induced skin papillomas. Loeliger, P., German Pat. No. 28543546, July 5, 1979; Loeliger, P., et al, Eur J Med Chemica Therapeutica, (1980) 15:9-15. The benzoic acid ethyl ester of these analogues also exhibits activity in the ODC assay, Dawson, M. I. unpublished data. However there is a problem in that the double bond in the propenyl moiety of these compounds is relatively unstable.
A principal aspect of this invention is to provide naphthyl or tetrahydronaphthyl substituted naphthoic analogues of retinoic acid which are biologically active, stable and which may exhibit lesser toxicity than other aromatic retinoic acid analogues.